• 11 y/o female

• Admission: 20091103

• 職業:學生• 種族:Chinese

• 旅遊史:無• 旅遊史:無• 接觸史:無• 群聚:無• 台東家裡種釋迦• 資料來源: patient and her mother

Chief Complaint

• Skin rash over legs for 5 days

Present Illness-1

• This 11-year-old girl came to OPD due to purpura over legs for several days

• discharged from Hospital 20091005-20091014

• Fresh blood in the sputum 3-4 days prior to last admissionadmission

– Mycoplasma pneumonia

– Iron deficiency anemia

– Asthma

– Suspect pulmonary tuberculosis

Present Illness-2

• Two months ago, she began to have spontaneous epistaxis for several times.

• Her purpura was noted but subsided several days later at that time

• lower leg pain while walking since two months • lower leg pain while walking since two months ago

• She couldn't walk on her own due to progressive muscle pain

• Lower leg edema and oral ulcers noted usually

• still mild cough with sputum recently

Past History

• just discharged 20091005 to 20091014

– Erythromycin

– Hb electrophoresis: no thalassemia

– Influenza A Ag: negative– Influenza A Ag: negative

– Acid fast stain of sputumXIII: negative

– LGI series due to bloody stool by S/A: normal

Family History

• No family history of TB

• Her older female cousin: SLE

Physical Examination

• T:36.4/℃ P:88/min R:18/min BP:129/91/mmHg

• 身高:144CM (20091103) 體重:34KG (20091103)

• consciousness: clear

• respiration: smooth

• Head: no trauma• Head: no trauma

• Neck: supple LAP: not enlarged

• ENT: np

• Conj:pale

• Sclerae: not icteric

• Throat: mild injected

• Tonsil: not enlarged

• Chest: symmetrical expansion, without chest wall retraction

• BS: bil coarse breathing sounds

• HS: RHB

• Abdomen: soft and flat• Abdomen: soft and flat

• Liver: impalpable

• Spleen: impalpable

• Bowel sound: normoactive

• Ext: lower leg muscle pain, no muscle atrophy,noarthralgia

• Skin: Purpura over lower legs

Laboratory Findings

11/19

• Bilateral feet swelling for four days and

purpura over legs for two days

Lung lesion, skin lesion and hematuria

• Common

– SLE

– Henoch-Schoenlein Purpura

– Atypical infection

Mycoplasma infection• Mycoplasma infection

• Less common

– Goodpasture's Syndrome

– Wegener's Granulomatosis

– Cryoglobulinemia

SLE• Criteria for diagnosis of systemic lupus erythematosus

– Malar rash: negative

– Discoid rash: over right leg by picture, no discoid rash now

– Photosensitivity: negative

– Oral ulcers: painless lip ulcer, subsided now (+)

– Arthritis: negative

– Serositis: negative– Serositis: negative

– Pericarditis: negative

– Renal disorder: Persistent proteinuria: 24 hrs protein: 413.6 mg 2+

– Neurologic disorder: negative

– Hematologic disorder Hemolytic anemia:• IDC:WEAKLY POSITIVE(1104)/D-COOMBS:NEGATIVE(1104)

• No reticulocytosis: RETICULCYT 1.20% (Auto:0.6~1.9% )

– Immunologic disorders: negative: Anti-ENA Screening : Negative

– Anti-DNA: negative: <12.0 IU/mL

– Antinuclear antibody: 1:40

• C3 123.00 mg/dL 90-180

• C4 21.80 mg/dL 10-40

• 檢查日期：2009/11/03(二)

• Normal Range Boderline

Anti-Beta2 Glycoprotein 1 IgG: 1.2 U/ml <10 10-15 Anti-Beta2 Glycoprotein 1 IgG: 1.2 U/ml <10 10-15

Anti-Cardiolipin IgG :2.6 GPL/ml <10 10-15

Anti-cardiolipin IgM :4.1 MPL/ml <10 10-15

LA . 40.9/32.7

Mixing Tes . 36.3/32.7

Comment S): NEGA LA

採檢日期時間:2009/11/06 05:40

T-CHOL 158 mg/dL <170 (<18Y)

TG 132 mg/dL 32-148 (>9Y-18Y)

FERRITIN 75.5 ng/mL F:10-291 M:22-322

Henoch-Schoenlein Purpura

• EULAR/PReS endorsed consensus criteria for the classification of childhood

vasculitides

• Ann Rheum Dis. 2006 Jul;65(7):936-41

Henoch-Schoenlein Purpura

• ESR: 67 MM/HR

• IgA: 273.00 mg/dL (131±60)

• Patients may have a normochromic anemia because of GIB

• Less hemolytic anemia

• In patients with incomplete or unusual presentations, a • In patients with incomplete or unusual presentations, a

biopsy of an affected organ (eg, skin or kidney) that

demonstrates leukocytoclastic vasculitis with a

predominance of IgA deposition confirms the diagnosis

• In children, renal disease is less prevalent/1.8 percent had

renal impairment

Atypical infection

Mycoplasma IgM IgG

1104 48.4 17.6

1110 47.5 15

1119 57.7 <10

Azithromycin on 11/4,5,6Doxycyclilne on 11/14-18

11/9 11/19

• A 6-year-old boy presented with an acute infection

caused by Mycoplasma pneumoniae associated with

respiratory tract and kidney involvement.

• Renal manifestations included acute nephritis with

decreased

• The child had an excellent outcome, with rapid

normalization of C3 and complete resolution of the acute

nephritis.• Pediatr Infect Dis J. 2003 Dec;22(12):1103-6.

• Acute nephritis and respiratory tract infection caused by Mycoplasma pneumoniae: case

report and review of the literature.

Atypical infection

• PPD test: negative

• EB-VCAG EQUIVOCAL 18.1 U/mL

• EB-VCAM NEGATIVE

• CMV IgG NEGATIVE 1.90 AU/mL

• CMV IgM NEGATIVE 0.25 INDEX• CMV IgM NEGATIVE 0.25 INDEX

• CMV-SV(U) NEGATIVE

• HCV AB NEGATIVE 0.42 S/CO

• ASLO 214.00 IU/mL H (< 200) on 11/6

• ASLO 209.00 IU/mL H (< 200) on 11/19

• Strepto.Ag-U NEGATIVE

Anti-GBM antibody (Goodpasture's)

disease• circulating antibodies are directed against the

NC1 domain of the alpha-3 chain of type IV

collagen, which is highly expressed in the GBM

and alveoli

• usually present with rapidly progressive

glomerulonephritis: acute renal failure, nephritic

urine sediment, and non-nephrotic proteinuria.

• Pulmonary involvement (alveolar hemorrhage) is

present in 60 to 70 percent of patients

Diagnosis of Goodpasture's disease

• demonstration of linear deposits of IgG (which

represent binding of anti-GBM antibodies to the

GBM) in the kidney biopsy specimen is

diagnosticdiagnostic

• Serologic testing for anti-GBM antibodies

• ANCA: almost always anti-myeloperoxidase, or

P-ANCA), since up to 40 percent of patients

with anti-GBM antibody disease also test

positive for ANCApositive for ANCA

• 11/12: P-ANCA(Anti-MPO): 1.2 U/ml

• 11/19: P-ANCA(Anti-MPO) : 0.6 U/ml

Wegener’s granulomatosis

• C-ANCA(Anti-PR3) : 36.4 U/ml• C-ANCA(Anti-PR3) : 36.4 U/ml

• Wegener's granulomatosis is a rare disease in childhood

• EULAR/PReS endorsed consensus criteria for the classification of childhood

vasculitides

• Ann Rheum Dis. 2006 Jul;65(7):936-41

11/12: C-ANCA(Anti-PR3): 32.4 U/ml11/19: 36.4 U/ml

• Subglottic, tracheal, or endobronchial stenosis

was added as a new criterion as these features

were noted to be frequent in childhood disease.

• CT is almost always a part of investigation, which • CT is almost always a part of investigation, which

no longer relies on a plain chest radiography

Computed tomography

• CT scanning has also shown the frequent presence of other findings that may suggest the diagnosis of vasculitis, including:

– Blood vessels leading to nodules and cavities (feeding vessels).

– Small peripheral, wedge-shaped densities suggesting pulmonary microinfarction

– Cuffing of the bronchovascular bundle in a lobar segmental and subsegmental distribution, often associated with narrowing of the bronchial lumen.

– Enlarged, irregular and stellate-shaped peripheral pulmonary arteries (the "vasculitis" sign)

Pediatr Nephrol. 2004 Apr;19(4):438-41

C-ANCA

• the sensitivity of cANCA: 28% to 92%,

depending on disease expression/specificity:

80% to 100%.

• A positive C-ANCA is usually present and helps • A positive C-ANCA is usually present and helps

distinguish isolated alveolar hemorrhage due

to Wegener's granulomatosis from other

causes, such as polyarteritis nodosa,

idiopathic pulmonary hemosiderosis, systemic

lupus erythematosus, and Goodpasture's

syndrome

Pathogeneses• Granulomatous reactions occur, possibly as the result of sensitized

T lymphocytes reacting with antigen and releasing various

cytokines that recruit macrophages to the site of injury.

• The activated macrophages release lysosomal enzymes and cause

local tissue injury

• The most commonly cited hypothesis for the role of ANCA in the • The most commonly cited hypothesis for the role of ANCA in the

pathogenesis of vascular injury is that an undetermined stimulus,

perhaps an infection, elicits inflammatory cytokines that induce

the expression of ANCA target antigens (proteinase 3 and/or

myeloperoxidase) on the neutrophil cell surface.

• The binding of ANCA to these antigens may cause degranulation

and respiratory burst of neutrophils, resulting in necrotizing

vasculitis

Diagnosis

• The diagnosis of Wegener's granulomatosisshould be confirmed by tissue biopsy at a site of active disease.

• Biopsy of a nasopharyngeal lesion (if present) is preferred because it is relatively noninvasivepreferred because it is relatively noninvasive

• However, in the small amount of tissue that can be removed in biopsies from this site, all pathologic features may not be seen

• Biopsy of the skin reveals a leukocytoclasticvasculitis with little or no complement and immunoglobulin on immunofluorescence.

Airway presentation-1

• The most common presenting symptoms and signs of Wegener's granulomatosis related to the upper airway include– Nasal crusting

– Sinus pain – Sinus pain

– Chronic rhinosinusitis

– Nasal obstruction

– Smell disturbances

– Purulent/bloody nasal discharge

– Excessive tearing (ie, epiphora)

– Sinus mucocele formation

Airway presentation-2

• Up to 1/3 of patients with pulmonary

involvement may have no noticeable

symptoms

• However, others present with cough, • However, others present with cough,

hemoptysis (due to alveolar hemorrhage

and/or tracheobronchial disease), dyspnea,

and pleuritic pain

Airway presentation-3

• These symptoms may be accompanied by

signs of pulmonary consolidation, pulmonary

nodules, and/or pleural effusion.

• Pulmonary symptoms in the absence of upper • Pulmonary symptoms in the absence of upper

respiratory tract symptoms or signs are

unusual.

CXR

• Nodules that may cavitate

• Alveolar opacities

• Diffuse hazy opacities

• Pleural opacities. • Pleural opacities.

Renal disease

• Renal biopsy reveals a segmental necrotizing

glomerulonephritis with few or no immune

deposits (pauci-immune) on

immunofluorescence and electron microscopyimmunofluorescence and electron microscopy

Other organ systems involved

• Joints (myalgias, arthralgias, arthritis)

• Eyes (conjunctivitis, episcleritis, uveitis)

• Skin (vesicular, purpuric, and hemorrhagic lesions, subcutaneous nodules)

• Nervous system (mononeuritis multiplex, cranial nerve abnormalities, external ophthalmoplegia, tinnitus, hearing abnormalities, external ophthalmoplegia, tinnitus, hearing loss)

• Heart (pericarditis, myocarditis, conduction system abnormalities)

• Less commonly, the gastrointestinal tract, subglottis or trachea, lower genitourinary tract (including the prostate or ureter), parotid glands, thyroid, liver, or breast

Prognosis-1

• The risk of venous thrombotic events, including deep venous thromboses or pulmonary emboli, also appears to be increased in ANCA-associated vasculitis

• Given that the kidney is a frequent target organ, progressive renal failure is commonly observed in patients with WG.

• End-stage renal disease eventually occurs in approximately 20 to 25 percent of patients

Prognosis-2

• The most serious complications include

tracheal or bronchial stenosis that can lead to

respiratory failure or postobstructive

pneumonia.pneumonia.

Cryoglobulinemia

• RYOGLO: POSITIVE IgG,IgM;WEAKLY POSITIVE IgA

• antibodies that precipitate from serum under

conditions of cold and resolubilize on rewarming

• Vasculitis results from the deposition of • Vasculitis results from the deposition of

cryoglobulin-containing immune complexes in

blood vessel walls and the activation of

complement.

• Approximately 40 percent of normal individuals possess

detectable CG, typically in concentrations of less than 80 µg/dL

• Demonstration of a persistently elevated cryocrit, such as

greater than 1 percent for three to six months Plus one or

more of the following:

– Clinical indicators of cryoglobulinemic vasculitis or

thrombosis, such as lower extremity purpura, particularly

with evidence of leukocytoclastic vasculitis on biopsy or with evidence of leukocytoclastic vasculitis on biopsy or

diminished serum C4 concentration

– Direct evidence of cryoglobulins from pathological

thrombotic or vasculitic specimens, such as by elution and

cryoprecipitation and/or immunofixation. While this direct

demonstration of CG may provide the most definitive

evidence, it is rarely sought in clinical practice.

• classified into types I, II, and III on the basis of

whether monoclonality and rheumatoid factor

activity (the ability to bind to the Fc portion of

IgG)

– RF 13.60 IU/mL (< 15)

– Type I cryoglobulins, which are monoclonal but lack – Type I cryoglobulins, which are monoclonal but lack

rheumatoid factor activity, are associated with certain

hematopoietic malignant neoplasms and often lead to

hyperviscosity rather than to vasculitis

– type II and type III cryoglobulins may be associated with

systemic vasculitis involving small (and often medium-sized)

blood vessels.

• Type II CGs are often due to persistent viral infections, particularly

hepatitic C and human immunodeficiency virus infections

Approximately 40 to 50 percent of all CG cases are

type III, and are often secondary to connective

tissue diseases

• Cryoglobulin types II and III are termed mixed • Cryoglobulin types II and III are termed mixed

cryoglobulins because they consist of both IgG

and IgM antibodies

• The IgM components in both type II and type III

cryoglobulinemia possess rheumatoid factor

activity (i.e., assays for rheumatoid factor are

positive)

• 90% of patients with vasculitis secondary to

mixed cryoglobulins are hypocomplementemic,

with C4 levels characteristically more

depressed than C3. depressed than C3.

• Infection with HCV accounts for at least 80% of

the vasculitis cases associated with mixed

cryoglobulins

• In a series of 40 patients with mixed

cryoglobulinemia and CV, a clinical triad

consisting of recurrent palpable purpura (100%),

polyarthralgias (73%), and renal disease (55%)

• 22 patients had clinical renal disease

manifesting as significant proteinuria, diastolic manifesting as significant proteinuria, diastolic

hypertension (64%), edema (77%), renal failure

(46%), and nephritic syndrome (22%)

• Pathology of glomerular disease showed

deposition of IgG, IgM, and complement, with

coexistent renal arteritis in 15 cases• Khasnis A - J Allergy Clin Immunol - 01-JUN-2009; 123(6): 1226-36

• Membranoproliferative glomerulonephritis

seems to be more common in mixed CG

• Isolated proteinuria or hematuria occur much

more frequently than nephrotic or nephritic more frequently than nephrotic or nephritic

syndromes or acute renal failure

• Most patients declare a chronic or rapidly

progressive disease course within three to five

years of diagnosis

• Skin lesions in mixed CG most often reveal

leukocytoclastic vasculitis (50 percent), less

commonly inflammatory or noninflammatory

purpura (10 to 20 percent)purpura (10 to 20 percent)

• Direct immunofluorescence microscopy of

acute lesions often reveals deposits of IgM,

IgG and/or C3 complement

Wegner’s granulomatosis and

Cryoglobulinemia

• RF and cryoglobulins, suggestive of the presence of

circulating IC, were detected respectively in 9 of 39

and 7 of 37 patients

• Haemolytic complement activity and complement

components were never decreased, but the C3d components were never decreased, but the C3d

breakdown product of C3 was elevated in all the 8

patients studied before treatment• Immunopathological studies of polyarteritis nodosa and Wegener's granulomatosis:

a report of 43 patients with 51 renal biopsies.

• Q J Med. 1983 Spring;52(206):212-23.

• renal deposition of CIC is transient, the

paucity of Ig deposits being due to rapid

clearance of IC by phagocytic cells; or

alternatively that vascular and glomerular alternatively that vascular and glomerular

lesions are not caused by CIC

• Wegener's granulomatosis. Electron microscopic and immunofluorescent studies.

• Hui AN, Ehresmann GR, Quismorio FP Jr, Boylen CT, Mayberg H, Koss MN.

• Chest. 1981 Dec;80(6):753-6.

• IgE may be interacting with basophils and

mast cells causing the release of vasoactive

substances which allow immune complexes to

deposit extravascularly.deposit extravascularly.

• Circulating immune complexes fall rapidly with

therapy

• The complexes are also capable of activating

complement with subsequent chemotaxis and

polymorphonuclear leukocytes.

• The leukocytes are able to phagocytose some • The leukocytes are able to phagocytose some

of the complexes, but in so doing release

proteolytic enzymes that can injure

surrounding tissue

Final diagnosis

• 1.Wegener’s granulomatosis

• 2.Cryoglobulinemia

• 3.Sinusitis

• Prednisolone 0.6 mg/kg/day

• Cyclophosphamide 1.5 mg/kg/day

• augmentin

CXR before discharge